IMPORTANT DISCLAIMER
Currently there are protocols for appropriate clinical trials for the therapy of a number of different forms of systemic/chronic chlamydial infections being prepared at Vanderbilt. The preliminary suggestions for chlamydial therapy contained within this document have been gleaned from early therapy for compassionate reasons and may not represent the final therapy. The use of these suggestions is similarly for compassionate therapy of patients suspected of having a systemic/chronic chlamydial infection. Finally, the information herewithin is proprietary.
Systemic/chronic chlamydial infections have been noted to have an associated secondary porphyria. Porphyrins, including water-soluble porphyrins (e.g., delta-aminolevulinic acid and porphyrobilinogen) and fat-soluble porphyrins (e.g, coproporphyrin III and protoporphyrin) may produce clinical episodes of porphyria. The presence of such porphyrins in an individual patient with chronic/systemic chlamydial infection can be confirmed pre- and during therapy by appropriate porphyrin tests such as obtaining 24-hour urine and 24-hour stool specimens for porphyrins.
It is recommended that a therapeutic regimen addressing porphyria should be instituted prior to the use of antimicrobial agents. This therapeutic regimen is aimed at controlling the chlamydial-associated secondary porphyria which may be present prior to antimicrobial therapy and/or may be triggered or increased during antimicrobial therapy of the chlamydial infection. This "porphyric reaction" to antimicrobial therapy should be recognized as such and differentiated from an expected cytokine-mediated immune response. Specific measures for the therapy of porphyria as derived from published medical literature on porphyria are employed and include:
1. High Carbohydrate Diet.
Approximately 70% of the daily caloric intake should be in the form of complex carbohydrates such as those found in bread, potato, rice, and pasta. The remaining 30% of calories in protein and fat ideally should be in the form of white fish or chicken.
2. High Oral Fluid Intake.
Drink plenty of oral fluids in the form of water (e.g., bicarbonated water or "sports-drinks" [water with glucose and salts]). This helps flush water-soluble porphyrins. Moreover, dehydration concentrates porphyrins and makes patients more symptomatic. The color of the urine should always be almost clear rather than dark yellow.
3. Avoid Red Meats.
Red meats, including beef and dark turkey as well as tuna and salmon contain tryptophan and should be avoided as much as possible.
4. Avoid Milk Products.
Milk products contain lactose and lactoferrin, both of which should be avoided as much as possible.
5. Glucose, Sucrose and Fructose.
Glucose is an important source of cellular energy: cellular energy is reduced with chlamydial infections. Increasing the availability of glucose provides optimal conditions for the cells to produce energy. However, sucrose is not the best way to increase the glucose availability. Sucrose is a mixture of glucose and fructose. Fructose is the sugar contained in fruit. Because high levels of fructose act as a signal to the liver to store glycogen, an excess may temporarily reduce the availability of glucose at the cellular level. Fructose should be avoided as much as possible. Instead, "sports-drinks" containing glucose (as well as containing important cations/anions) can be used. Glucose tablets also can be used.
6. Avoid Alcohol.
Alcohol is a well known aggravator of porphyria and should be avoided as much as possible.
Vitamins/Antioxidants/Supplements
7. B-Complex Vitamins.
Glucose is needed by host cells infected by chlamydiae. The availability of glucose is assisted by taking B-complex vitamins. These include folic acid (400 mcg twice per day), vitamin B-1 (thiamin 10 mg twice per day), vitamin B-2 (riboflavin 10 mg twice per day), vitamin B-5 (pantothenate 100 mg twice per day), vitamin B-6 (pyridoxine 100 mg twice per day or pyridoxal-5 phosphate 25 mg twice per day), and vitamin B-12 (500 mcg sublingual three time per day).
8. Antioxidants.
Antioxidants and related agents should be taken twice per day. These should include vitamins C (1 gram twice per day) and E (400 units twice per day) as well as L-carnitine (500 mg twice per day), ubiquinone (coenzyme Q10; 30 mg twice per day), quercetin 400 - 500 mg twice per day, biotin (5 mg twice per day), and lipoic acid (400 mg twice per day). Bioflavinoids (also called proanthocyanidins; pycnoginol is an example of these antioxidants) are also very effective. Selenium (100 mcg twice per day) should be taken with the vitamin E. Glutamine (2 - 4 grams twice per day), glucosamine (750 - 1000 mg two or three times per day) and chondroitin sulfate (250 - 500 mg twice per day) should also be included.
Antiporphyrinic Drugs
9. Benzodiazepine Drugs.
The specific benzodiazepine drugs used depends, in part, on the symptoms. If panic attacks are the problem, xanax (0.5 mg three or four times per day) can be used. If sleeping is a problem, restoril (30 mg at night) can be used.
10. Hydroxychloroquine.
Hydroxychloroquine (100 - 200 mg once or twice per day) is often used to treat porphyria. For patients with symptoms of porphyria, a single 100 mg dose of hydroxychloroquine may be tried. If this trial dose relieves the symptoms, hydroxychloroquine may be continued. The hydroxychloroquine dose must be adjusted for each patient. This is done by increased the dose slowly, starting with 100 mg every other day, then slowly increasing to a maximum dose of no more than 200 mg twice per day. Most patients do well on 100 mg once per day. Visual/
eye exams should be done periodically as per manufacturer's recommendations (See PDR).
Miscellaneous
11. Oral Activated Charcoal.
Activated charcoal absorbs fat-soluble porphyrins. Treatment with oral activated charcoal, which itself is nonabsorbable, binds these porphyrins in the gastrointestinal tract and hence prevents them from being reabsorbed in the small intestine. At least 2 grams (eight 250 mg capsules) of activated charcoal should be taken three times per day on an empty stomach (i.e., 2 hours after and 2 hours before a meal). Much more activated charcoal can be safely taken; up to 20 grams six time a day for nine months has been taken without any adverse side effects. It is important that this charcoal be taken on a completely empty stomach without any food, vitamins, or medications taken within 2 hours before or 2 hours after charcoal ingestion as the charcoal may absorb the food, vitamins, or drugs as well as the porphyrins.
II. THERAPEUTIC REGIMEN FOR VITAMIN B12 DEFICIENCY.
Many patients with systemic/chronic chlamydial infection appear to have an subtle and unrecognized vitamin B12 deficiency at the cellular level. This can be documented in an individual patient by obtaining both a vitamin B12 level (usually normal or low) and serum homocysteine and methylmalonate levels (one or both of these will be high). This vitamin B12 deficiency can corrected by high-
dose vitamin B12 therapy as follows:
1. Vitamin B12 Therapy Prior to Chlamydial Therapy.
Adults normally have approximately 3,000 mcg of vitamin B12 in body stores, mostly in the liver. Initial vitamin B12 therapy before chlamydial therapy includes replacement therapy for any vitamin B12 deficit in these body stores. Therefore, over the first several days of antiporphyrin therapy, 6,000 mcg of parental (intramuscular or subcutaneous) vitamin B12 is given. For each of the next 3 weeks, 6,000 mcg of parental vitamin B12 is given once per week.
2. Vitamin B12 Therapy During Chlamydial Therapy.
Chlamydial antimicrobial therapy is associated with increased need for vitamin B12. Therefore, 3,000 mcg of parental vitamin B12 is given once per week while the patient is receiving antimicrobial therapy for systemic/chronic chlamydial infection. This is in addition to the 1,500 mcg of sublingual vitamin B12 taken each day.
3. Vitamin B12 Therapy Post Chlamydial Therapy.
Following the completion of antimicrobial therapy of systemic/chronic chlamydial infection, the vitamin B12 and serum homocysteine/methylmalonate levels should be rechecked. If these are low, it suggests a continued vitamin B12 deficiency. Oral therapy with 1,500 mcg of sublingual cobalamin per day should be continued. After several months, 2,000 mcg of parental vitamin B12 may be given as a therapeutic trial. If the patient's energy is not increased by the parental dose, continued therapy with sublingual vitamin B12 is probably adequate. Periodic trials of parental vitamin B12 can be used to assess the sublingual therapy.
III. THERAPEUTIC ANTIMICROBIAL REGIMEN.
When the presence of chlamydia in the blood is detected by culture and/or PCR and active infection is suspected per elevated IgM and IgG antibody titers, a presumptive diagnosis of systemic/ chronic chlamydial infection can be made.
Step 1: Patient education begins with an explanation of the clinical significance of the test results and the potential for associated effects such as porphyria and vitamin B12 deficiency. Initial blood work is obtained for the following tests: 1) CBC, 2) liver function tests, 3) uric acid, and 4) serum iron studies. Other useful tests include: red blood cell ALA dehydratase, red blood cell PBG deaminase, vitamin B-12 level, serum homocysteine level, and serum methymalonate level. A 24 hour urine and stool may be collected for porphyrins.
Step 2: Next, the patient is placed on the antiporphyric regimen and vitamin B12 therapy before the antibiotics are started. This is continued throughout the antimicrobial therapy and is an important component as it minimizes cellular damage and facilitates cellular repair.
Step 3: Following this, the first antimicrobial agent is started. This agent is amoxicillin (500 mg q 12 hours) which is combined with probenecid (500 mg q 12). If the patient is penicillin-allergic, penicillamine (125 mg q 12 hours) is substituted for the amoxicillin. In either case, the probenecid is used to potentiate the serum/intra-cellular levels of amoxicillin/penicillamine. Chlamydial cell walls have LPS and other antigens which can stimulate the immune system when released by antimicrobial therapy. This can range from cytokine-mediated mild flu-like symptoms to a more severe Jarisch-Herxheimer-like reaction. Therefore, it is best to start the amoxicillin first and then gradually add the probenecid. This is done by giving amoxicillin once per day on only one day for the first week, then twice a week, three times a week and then every day. The amoxicillin is then increased to twice per day using the same schedule. The probenecid is added using the same schedule. The patient is closely monitored on these first two agents for side effects. These agents are continued for the entire course of chlamydial therapy.
Step 4: After the patient has adjusted to the amoxicillin/probenecid therapy, a second combination of antimicrobial agents directed at replicating chlamydiae is added. This combination, like the first, is introduced very gradually, being given initially once per day on only one day per week. Once this combination therapy is well tolerated (This may take 2-4 weeks or longer.), the antimicrobial combination is increased to twice per week, given on Monday and Friday with continued monitoring for side effects. After 2-4 weeks or more of this twice-per-week combination therapy, the antimicrobial combination is increased to three times per week, given on Monday, Wednesday, and Friday. This triweekly combination therapy is continued until tolerated before being increased to daily combination therapy.
The combination of antimicrobial agents added to the amoxicillin/probenecid (or penicillamine/probenecid) is either bactrim (one double strength bactrim twice per day) and isoniazid (300 mg once per day), or levofloxacin (500 mg once per day) and isoniazid 300 mg once per day). The bactrim/INH regimen is the least expensive and seems to be well tolerated. Patients with sulfa allergies, of course, will require levaquin rather that bactrim. For patients with a history of hepatitis, or other potential liver problems, INH is continued MWF even after the bactrim DS is advanced to twice per day. Moreover, liver function studies should be followed in patients receiving INH. Azithromycin (500 mg once per day) may be substituted for the isoniazid in these patients.
Step 5: The duration of therapy is based on the results of repeated testing for the presence of chlamydiae. Repeat blood tests for chlamydia are recommended every four months. The goal is a negative whole-blood PCR for chlamydia (Blood collected in citrated tube.), negative IgM titers (< 1:50), and low IgG titers (< 1:200) (Blood collected in red top tube.).